Reliability and validity of the Nepean Beliefs Scale for delusions and overvalued ideas in chronic schizophrenia: analysis of a preliminary pilot study.

Introduction: The Nepean Beliefs Scale by Brakoulias et al. is an interview-based multidimensional instrument that measures pathological beliefs in various psychiatric disorders. This study examined the reliability and validity of Nepean Beliefs Scale (NBS) for delusions and overvalued ideas in patients with chronic-phase schizophrenia. Methods: Multiple raters at two healthcare settings examined the beliefs of 28 individuals with schizophrenia using the NBS. Concurrently, PANSS, PDI-21, BCIS, PHQ-9 and GAD-7 were administered. Results: The NBS had high reliability and correlation with relevant scales. Discussion: The NBS was found to have sufficient reliability and validity for assessing the pathological beliefs of patients with chronic schizophrenia. Although NBS is an easy-to-instruct instrument, it should be noted that appropriate explanations and examples should be added to instructions to obtain reliable responses from patients with chronic schizophrenia.

Postoperative Medial Tilting of the Joint Line and Preoperative Kinematics Influence Postoperative Medial Pivot Pattern Reproduction in Total Knee Arthroplasty.

Background: Reproducing the medial pivot pattern after total knee arthroplasty (TKA) is known to improve patient satisfaction. However, the factors affecting the postoperative medial pivot pattern in TKA are controversial. The purpose of this study was to examine the factors affecting the postoperative medial pivot pattern in posterior-stabilized TKA. Methods: This study involved 30 cases with knee osteoarthritis who underwent primary posterior-stabilized TKA. The preoperative and postoperative kinematics were measured using a computed tomography-free navigation system, and the patients were divided into the following 2 groups: the medial pivot pattern (MP) group and non-medial pivot pattern (non-MP) group. In addition, we measured each of the following angles on X-ray films (preoperative and postoperative femorotibial angle, hip-knee-ankle angle, mechanical lateral distal femoral angle, medial proximal tibial angle). We examine the factors affecting the postoperative medial pivot pattern. Results: There were 14 cases in the MP group and 16 cases in the non-MP group at the preoperative knee kinematic assessment and 17 cases in the MP group and 13 cases in the non-MP group at the postoperative knee kinematic assessment. The preoperative kinematic pattern was conserved after the surgery at a rate of 76.7%. The postoperative MP-group showed a significantly smaller preoperative femorotibial angle and hip-knee-ankle and a significantly smaller postoperative mechanical lateral distal femoral angle and medial proximal tibial angle in comparison to the postoperative non-MP group. Conclusions: Preoperative kinematics and postoperative mechanical lateral distal femoral angle and medial proximal tibial angle may be important factors that affect the postoperative medial pivot pattern.

Effect of individualized occupational therapy on social functioning in patients with schizophrenia: A five-year follow-up of a randomized controlled trial.

This study aimed to evaluate the long-term effects of adding individualized occupational therapy (IOT) to a three-months group occupational therapy (GOT) on social functioning in inpatients with schizophrenia or schizoaffective disorder at a follow-up investigation five-years after discharge. Initially, patients were randomly assigned to GOT + IOT or GOT alone, with 102 patients, 48 in GOT + IOT and 54 in GOT alone, completing the five years follow-up. The primary outcome was change in social functioning assessed by the Social Functioning Scale (SFS) from baseline to five-year follow-up. Other outcomes included Brief Assessment of Cognition in Schizophrenia (BACS), Schizophrenia Cognition Rating Scale (SCoRS), Intrinsic Motivation Inventory (IMI), Global Assessment of Functioning (GAF), Positive and Negative Syndrome Scale (PANSS), and Client Satisfaction Questionnaire-8 (CSQ-8). There were significant improvements for the GOT + IOT group over GOT in the SFS total score, which could be explained by improvements in withdrawal/social engagement, interpersonal communication, pro-social activities, recreation, and independence-competence. Multiple regression analysis showed that the period from hospitalization to commencing occupational therapy, type of occupational therapy, BACS motor speed, BACS executive function, and IMI interest/enjoyment were significantly associated with SFS total score. Our findings suggest that adding IOT to GOT may improve the long-term outcome on social functioning in schizophrenic patients. However, the long time period between intervention and follow-up and the unavailability of treatment information during the follow-up period has to be mentioned as a limiting factor of this study.

Calcium/calmodulin-dependent protein kinase IIα heterozygous knockout mice show electroencephalogram and behavioral changes characteristic of a subpopulation of schizophrenia and intellectual impairment.

Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKIIα heterozygous mouse (CaMKIIα-hKO). The current study characterizes behavioral phenotypes of CaMKIIα-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKIIα-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKIIα-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time-frequency EEG oscillations. CaMKIIα-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time-frequency measures. Additionally, CaMKIIα-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2+ channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKIIα-hKO mice likely model a subpopulation of patients with schizophrenia.

Aerobic exercise and cognitive functioning in schizophrenia: An updated systematic review and meta-analysis.

This study serves as an update to a recent systematic review and meta-analysis to summarize the effect of aerobic exercise on cognition in schizophrenia and determine the most effective method of aerobic exercise. We searched for controlled studies investigating the effect of aerobic exercise on cognition in schizophrenia published until January 2021. Fifteen studies were included. A random-effects model was used to estimate the standardized mean differences (SMDs) between cognitive outcomes of aerobic exercises and controls. Compared with controls, aerobic exercises resulted in significant improvements in global cognition (SMD = 0.21), attention/vigilance (SMD = 0.32), working memory (SMD = 0.27), and verbal learning (SMD = 0.30). Significant improvements in global cognition were observed with group exercise (SMD = 0.28), exercise supervised by exercise professionals (SMD = 0.27), as well as with ≥ 90 min/week (SMD = 0.26) and ≥ 12 weeks duration (SMD = 0.22). Our findings provide information beneficial for determining the most effective aerobic exercise method to improve cognition in schizophrenia.

Mite avoidance decreased mite-specific IgE levels and ameliorated asthma symptoms in subjects who lived in temporary housing after natural disasters

Background: We previously reported an increased prevalence of asthma among patients who had lived in temporary housing after the 2011 Great East Japan Earthquake. We investigated the prognosis of asthma in former residents of temporary housing after allergen avoidance. Methods: Asthma was diagnosed in adults ≥ 15 years from 2014 to 2019 who had lived in temporary housing in Ishinomaki City for at least 1 year. The disease prognosis after the intervention of allergen avoidance in cases that were followed for more than 3 years during the 6-year study period was analyzed. We measured the Dermatophagoides farinae -specific immunoglobulin E (IgE) levels in serum, and the amount of Dermatophagoides group 1 (Der 1) antigen on their futons or mattresses. We instructed residents in an allergen avoidance strategy that included 32 tasks, including using microfiber bedding covers. Results: Of the 202 examinees who were followed for at least 3 years during the 6-year study period, 72(35.6%) were asthmatic during at least one examination. Of these 72 asthmatics, 55(76.4%) developed the disease after the earthquake, and more than half of the cases that we diagnosed at the examination were mild intermittent asthma. After the allergen-avoidance intervention, both the Der 1 level on the futons or mattresses of residents who were diagnosed with asthma but who were nonasthmatic at the final screening and their serum Der f-specific IgE levels significantly decreased (P < 0.01) at the final examination. Conclusion: Antigen avoidance ameliorated mild asthma that was prevalent among residents of temporary housing after the earthquake (AU)

Aerobic exercise and cognitive functioning in schizophrenia: Results of a 1-year follow-up from a randomized controlled trial.

We previously reported that adding combined, individual, and group aerobic exercise (AE) interventions to the treatment as usual (TAU) for schizophrenia showed significant improvements in cognition and other outcomes compared to those with TAU alone in a randomized controlled trial. Following the promising results of our previous study, this 1-year follow-up study evaluated the improvements in cognition and other outcomes with TAU + AE compared to those with TAU alone. Of 41 randomized patients, 40 were included in the intent-to-treat population-20 in the TAU + AE and 20 in the TAU alone; all patients completed the 1-year follow-up. Mixed models were applied to assess changes in outcome measures over time from baseline to 1-year follow-up. At 1-year follow-up, the TAU + AE demonstrated significant group by time interaction effects in several cognitive domains, intrinsic motivation, negative symptom, interpersonal relations, and functional outcome compared with the TAU alone. Our results demonstrate that the improvements in cognition and other outcomes with TAU + AE were maintained and that functional outcome improved over 1-year follow-up. These findings show that the improvements sustained for each outcome over 1 year have the potential to offer opportunities for greater transitions to improvement of functional outcome.

The efficacy of extended metacognitive training for psychosis: A randomized controlled trial.

This study investigated the efficacy of 10-module metacognitive training (MCT) among Japanese patients with schizophrenia by conducting a multicenter randomized controlled trial to test the influence of the most recent and extended version of MCT on positive symptoms. A six-center, randomized, assessor-blind, controlled trial between "treatment as usual" (TAU) and TAU + MCT was conducted. Fifty inpatients and outpatients with schizophrenia, schizotypal, and delusional disorders (ICD 10) were enrolled, then randomly assigned to TAU (n = 26) or TAU + MCT (n = 24). Assessments were made at baseline, after six weeks, immediately posttreatment, and 1-month post-treatment. The primary outcome was positive symptom score, as measured by the Positive and Negative Syndrome Scale (PANSS). General assessment of functioning (GAF) and measures of cognitive biases were secondary outcomes. Completion at post-treatment (10 weeks later) and 1-month follow-up was high-TAU + MCT, n = 22 (91.67%) and TAU, n = 23 (88.46%). The severity of PANSS positive symptoms declined significantly in the TAU + MCT treatment group compared with the TAU group. GAF also showed significantly greater improvement in the TAU + MCT group compared with the TAU group. There was also a trend for greater efficacy of MCT on cognitive biases. In conclusion, this study provides support for the efficacy of 10 module MCT concerning positive symptomatology (especially, delusion) and general functioning.

Aerobic exercise and cognitive functioning in schizophrenia: A pilot randomized controlled trial.

This pilot randomized controlled trial evaluated the combined effect of individual and group aerobic exercises (AEs) on cognition in schizophrenia. Among 32 randomized patients, 31 were included in the intent-to-treat population: 16 in treatment as usual (TAU) + AE and 15 in TAU groups. Over 12 weeks, patients were given a dose of 2 exercise sessions per week, including 1 individual session and 1 group session. TAU + AE patients showed significant improvements in cognition, intrinsic motivation, psychiatric symptoms, and interpersonal relations. These encouraging findings support the promise of integrated individual and group AEs to improve cognition and other outcomes in schizophrenia.

Effect of adding individualized occupational therapy to standard care on rehospitalization of patients with schizophrenia: A 2-year prospective cohort study.

AIM: We examined the effect of individualized occupational therapy (IOT) compared to the usual group occupational therapy (GOT) on the rehospitalization of patients with schizophrenia. METHODS: A prospective cohort study included patients with schizophrenia who were discharged within 1 year from a psychiatric hospital. Time to rehospitalization by treatment group (GOT + IOT or GOT-alone) was evaluated with Kaplan-Meier survival analysis. The impact of demographics and clinical factors associated with rehospitalization was investigated using Cox proportional hazards models. RESULTS: Of the 111 patients who met the criteria, 54 were in the GOT + IOT group and 57 in the GOT-alone group. Over the 2 years from discharge, the overall rehospitalization rate was 51.376% (56 patients); the GOT + IOT group demonstrated a significantly lower rehospitalization rate with 16 patients rehospitalized compared to 40 patients from the GOT-alone group. Time to rehospitalization was significantly longer for the GOT + IOT group compared to those in the GOT-alone group (P < 0.001). The multivariate Cox proportional hazards models showed that type of occupational therapy (hazard ratio [HR] = 0.543), medication adherence (HR = 0.343), access to resident support persons (HR = 0.450), and executive function at discharge (HR = 0.740) were all significantly associated with rehospitalization. CONCLUSION: Our results provide support for the prolonging effects of IOT in relation to rehospitalization and the reduction of rehospitalization risk compared to patients with schizophrenia who receive GOT alone, in addition to supporting good cognition at discharge and favorable medication adherence.

Correction: A multicenter, randomized controlled trial of individualized occupational therapy for patients with schizophrenia in Japan.

[This corrects the article DOI: 10.1371/journal.pone.0193869.].

A multicenter, randomized controlled trial of individualized occupational therapy for patients with schizophrenia in Japan.

The individualized occupational therapy (IOT) program is a psychosocial program that we developed to facilitate proactive participation in treatment and improve cognitive functioning and other outcomes for inpatients with acute schizophrenia. The program consists of motivational interviewing, self-monitoring, individualized visits, handicraft activities, individualized psychoeducation, and discharge planning. This multicenter, open-labeled, blinded-endpoint, randomized controlled trial evaluated the impact of adding IOT to a group OT (GOT) program as usual for outcomes in recently hospitalized patients with schizophrenia in Japanese psychiatric hospitals setting compared with GOT alone. Patients with schizophrenia were randomly assigned to the GOT+IOT group or the GOT alone group. Among 136 randomized patients, 129 were included in the intent-to-treat population: 66 in the GOT+IOT and 63 in the GOT alone groups. Outcomes were administered at baseline and discharge or 3 months following hospitalization including the Brief Assessment of Cognition in Schizophrenia Japanese version (BACS-J), the Schizophrenia Cognition Rating Scale Japanese version, the Social Functioning Scale Japanese version, the Global Assessment of Functioning scale, the Intrinsic Motivation Inventory Japanese version (IMI-J), the Morisky Medication Adherence Scale-8 (MMAS-8), the Positive and Negative Syndrome Scale (PANSS), and the Japanese version of Client Satisfaction Questionnaire-8 (CSQ-8J). Results of linear mixed effects models indicated that the IOT+GOT showed significant improvements in verbal memory (p <0.01), working memory (p = 0.02), verbal fluency (p < 0.01), attention (p < 0.01), and composite score (p < 0.01) on the BACS-J; interest/enjoyment (p < 0.01), value/usefulness (p < 0.01), perceived choice (p < 0.01), and IMI-J total (p < 0.01) on the IMI-J; MMAS-8 score (p < 0.01) compared with the GOT alone. Patients in the GOT+IOT demonstrated significant improvements on the CSQ-8J compared with the GOT alone (p < 0.01). The present findings provide support for the feasibility in implementing an IOT program and its effectiveness for improving cognitive impairment and other outcomes in patients with schizophrenia.

Development of an Individualized Occupational Therapy Programme and its Effects on the Neurocognition, Symptoms and Social Functioning of Patients with Schizophrenia.

We described an individualized occupational therapy (IOT) programme and examined the effects of adding IOT to group OT (GOT) on improving neurocognition, symptoms and social functioning among recently hospitalized patients with schizophrenia. The Brief Assessment of Cognition in Schizophrenia-Japanese version (BACS-J), the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning scale were used for outcome evaluations. Fifty-one patients were voluntarily assigned to either the GOT + IOT (n = 30) or GOT alone (n = 21) groups based on their preferences. Retention in the GOT + IOT group was 100%. Three-month baseline to discharge assessments in the GOT + IOT group showed significant improvements in BACS-J verbal memory, working memory, verbal fluency, attention, executive function and composite score, and in PANSS positive subscale, general psychopathology subscale, and total score compared to the GOT alone group. Study limitations notwithstanding, the present findings provide preliminary support for the feasibility of implementing IOT and its effectiveness for improving cognitive impairment and symptoms in patients with schizophrenia. The results of this study indicate that IOT in psychiatric facilities may improve psychosocial treatment of schizophrenia. Additional study is warranted to replicate the effects of IOT as demonstrated in this Japanese study. Copyright © 2016 John Wiley & Sons, Ltd.

Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity.

Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNFα, in epididymal, but not subcutaneous, fat depots. When NK cells were depleted either with neutralizing antibodies or genetic ablation in E4bp4(+/-) mice, obesity-induced insulin resistance improved in parallel with decreases in both adipose tissue macrophage (ATM) numbers, and ATM and adipose tissue inflammation. Conversely, expansion of NK cells following IL-15 administration or reconstitution of NK cells into E4bp4(-/-) mice increased both ATM numbers and adipose tissue inflammation and exacerbated HFD-induced insulin resistance. These results indicate that adipose NK cells control ATMs as an upstream regulator potentially by producing proinflammatory mediators, including TNFα, and thereby contribute to the development of obesity-induced insulin resistance.

Factors Influencing Rehospitalisation of Patients with Schizophrenia in Japan: A 1-year Longitudinal Study.

OBJECTIVE/BACKGROUND: This longitudinal study explored factors influencing the rehospitalisation of patients with schizophrenia in Japan. METHODS: Participants comprised patients with schizophrenia who were discharged from a psychiatric hospital in Japan. The investigations were conducted at the time of discharge and one year later. Demographics and clinical characteristics included the following: the type of occupational therapy (OT) interventions (group and individualized or group only); the assessment scales' scores on hospitalisation; the community living conditions after discharge; and the contents of outpatient treatment (outpatient OT, day-care treatment, home-visit nursing, and adherence to outpatient treatment and medication). All variables were examined in a binomial logistic regression analysis to identify the factors for rehospitalisation. RESULTS: The rehospitalisation rate was 31.8%, as 14 of 44 participants were rehospitalised within one year after discharge. The type of OT interventions (OR = 7.05, 95% CI = 1.36 -36.69, p = .020) and the adherence to outpatient treatment and medication (OR = 9.48, 95% CI = 1.82-49.33, p = .008) were significant contributing factors to rehospitalisation. CONCLUSION: This study provided preliminary support for the finding that individualized occupational therapy and proper adherence to outpatient treatment and medication are associated with reducing the rehospitalisation of patients with schizophrenia in Japan.

ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia.

We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in cAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics.

Des-acyl ghrelin protects microvascular endothelial cells from oxidative stress-induced apoptosis through sirtuin 1 signaling pathway.

OBJECTIVE: Ghrelin is a stomach-derived hormone. Acylation of ghrelin has been essential for its biological activities such as stimulating appetite. On the other hand, the function of des-acyl ghrelin (Des-G) has not been fully elucidated. The aim of the present study is to examine the anti-apoptotic effect of Des-G on endothelial cells. MATERIALS/METHODS: After human retinal microvascular endothelial cells (RMECs) were pretreated with or without 100nmol/L Des-G, apoptosis was induced with 0.1mmol/L hydrogen peroxide (H2O2). For pharmacological inhibition of surtuin 1 (SIRT1) catalytic activity, the cells were treated with 10µmol/L Ex-527. Inhibition of SIRT1 with siRNA was also performed. The quantitative estimation of DNA fragmentation was used as a marker of apoptosis. Furthermore, total SIRT activity in nuclear extracts, mRNA and protein levels of SIRT1, manganese superoxide dismutase (MnSOD) and catalase were determined. RESULTS: Des-G pretreatment protected RMECs from oxidative stress-induced apoptosis and increased SIRTs deacetylase activity in nuclear extracts. On the other hand, both pharmacological and siRNA mediated inhibition of SIRT1 attenuated the anti-apoptotic effect of Des-G. Moreover, Des-G increased mRNA and protein levels of SIRT1 and antioxidant enzymes such as MnSOD and CAT, which are downstream targets of SIRT1. Although the treatment of Ex-527 did not alter mRNA expression levels of SIRT1, it decreased mRNA expression levels of antioxidant enzymes in the cells with Des-G pretreatment. CONCLUSIONS: Our results suggest that SIRT1 signaling pathway contributes to protective effect of Des-G against oxidative stress-induced apoptosis.

Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone.

It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD)-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi)), whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.

Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus.

AIMS/INTRODUCTION: The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel is a key component of insulin secretion in pancreatic ß-cells. Activating mutations in ABCC8 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent NDM (PNDM). MATERIALS AND METHODS: The coding regions and conserved splice sites of KCNJ11,ABCC8 and INS were screened for mutations in a 12-year-old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch-clamp experiments in COS-1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas in vitro and in the patient. RESULTS: We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in ABCC8. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch-clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas in vitro and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide. CONCLUSIONS: We identified the Pro1198Leu ABCC8 mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM.